Abstract 1260: Acute Metformin Therapy Confers Cardioprotection Via an AMPK-eNOS-Dependent Pathway
Background: Clinical reports indicate that the widely used anti-hyperglycemic drug, metformin, reduces cardiovascular end points of type 2 diabetics by actions that cannot be solely attributed to its glucose-lowering effects. The pleiotropic effects of metformin are mediated in part by its activation of AMP-activated protein kinase (AMPK), a metabolite sensing protein kinase whose activation following myocardial ischemia is thought to be an endogenous protective signaling mechanism. We sought to investigate the potential cardioprotective effects of acute metformin treatment in a non-diabetic murine model of myocardial ischemia-reperfusion (MI-R) injury.
Methods: Mice were subjected to transient myocardial ischemia for a period of 30 min followed by 24 hr of reperfusion. A sub-therapeutic dose of metformin (125 μg/kg) or vehicle (saline) was administered intravenously at the time of reperfusion.
Results: No changes in blood glucose were observed with metformin. Following MI-R, metformin reduced the rise in serum troponin-T by 56% (p=0.026), reduced infarct size by 49% (p<0.001), and preserved left ventricular structure and function when compared to vehicle treated mice. During early reperfusion, we observed an increase in the phosphorylation and activity of AMPK. Treatment with metformin augmented this MI-R-induced increase in AMPK activation and also significantly increased endothelial nitric oxide (eNOS) phosphorylation at residue serine 1177.
Conclusions: These findings provide important information that myocardial AMPK activation by metformin following MI-R sets into motion events, including eNOS activation, which results in cardioprotection.